Diabetes is a major risk factor for cardiovascular diseases and diabetics have a significantly greater frequency of cardiovascular disorders. As a consequence, diabetics are more prone to undergo surgery for repair or replacement of tissues such as blood vessels and heart valves. Tissue engineered constructs based on scaffolds and autologous progenitor cells are currently being developed, but very little information exists regarding the fate of tissue engineered devices in the compromised patient, and more specifically in diabetic environments. Results obtained from implantation studies in healthy animals have served as benchmarks for FDA approval;however, some tissue engineered implants have failed dramatically in clinical trials. Notably, it is well documented that the outcome of reparative surgery and organ and tissue transplantation is more problematical in diabetic patients. Diabetes is characterized by elevated levels of blood glucose, which interacts irreversibly with proteins, lipids and nucleic acids via oxidation and cross linking processes, resulting in formation of advanced glycosylation end products (AGEs). Glycoxidation induces severe cell and matrix alterations that result in endothelial dysfunction, accelerated atherosclerosis, activation of inflammation, fibrosis and impaired healing, all of which are not conducive to the desired integration and remodeling of tissue engineered constructs. Our long-term goal is to develop constructs adapted to withstand high glucose and oxidative stress typical of diabetes. Our working hypothesis, robustly supported by preliminary data, is that both scaffolds and cells are susceptible to diabetes-induced complications and that chemical stabilization of scaffolds would improve the outcome of tissue engineering in diabetes. To test this hypothesis we propose to test constructs in diabetic models and compare their properties to non-diabetic control environments. In Aim 1, scaffolds will be prepared from decellularized cardiovascular tissues and their susceptibility to diabetes-induced complications evaluated in vivo and in vitro models of diabetes. In Aim 2, scaffolds treated with polyphenol stabilizing agents prepared as "diabetes-resistant" constructs will be evaluated for resistance to diabetes-induced alterations in same animal models. Finally, for Aim 3 mesenchymal stem cells will be obtained from diabetic animals and those will be re- implanted as scaffold-supported autologous implants. PUBLIC HEALTH RELEVANCE: Almost 25 million Americans have diabetes, a dreadful disease which is simply characterized by high levels of blood sugar (glucose). Excessive glucose binds to tissues and cells and this binding reduces the activity of the heart muscle, heart valves, blood vessels, kidneys, and nerves. For this reason, patients with diabetes have much higher risks of cardiovascular and other diseases, as compared to non-diabetics. Surgery is required to replace diseased heart valves and arteries with artificial implants, but these implants fail after 15-20 years because they are made of non-living materials. New and improved devices are needed for millions of cardiovascular patients every year. To make better implants, we are developing living materials comprised of layers of tissue scaffolds to which we add the own patients'stem cells. Although practically all cardiovascular devices have been tested in normal healthy animals, our main concern is that implantation of tissue scaffolds and cells into diabetic patients will expose the implants to high glucose levels and damage the implants. Our ideas are based on clinical studies which have shown that tissue transplants in diabetics have many more problems in diabetics as compared to non-diabetics. Thus we propose to study the effect of diabetes on tissue scaffolds and stem cells by using animal models of diabetes. In an attempt to solve this problem, we also propose to treat the scaffolds with chemicals that protect the scaffolds and make them resistant to diabetes. These studies have not been done before and will provide a guiding light for future development of implants for patients with diabetes.